Increased regulatory expectations and the need to mitigate risk have popularized the use of redundant filtration for bulk and final fill operations. Single-use redundant filtration (SURF) assemblies are an efficient and flexible alternative to stainless steel systems because they eliminate clean-in-place (CIP), sterilization steps and the associated validation protocols. Preparation time can also be significantly reduced when using single-use assemblies because of their presterilized format and the ease with which they can be handled. Redundant filtration operations in multiproduct facilities can be performed without spending the extra validation time that is often required for non-disposable systems.

This article identifies a suitable design for redundant filtration operations using single-use technology and standardized assembly components. The design was finalized with input from a global technical and quality team with consideration given to international regulatory requirements. The article also demonstrates the capability of the assembly to withstand the high pressure that is used for integrity testing and drying. Pre-use integrity testing was performed on both filters. Using hydrophilic/hydrophobic filters on the assembly outlet eliminated flush volume limitations caused by catch bag size. Assembly specifications, such as leachables and extractables, hold up volume and flushing requirements, were established for a single-use assembly.

MEETING REGULATORY EXPECTATIONS

As defined in PDA Technical Report 26, redundant filtration is a "type of serial filtration in which a second sterilizing-grade filter is used as a backup in the event of an integrity failure of the primary sterilizing filter." The pore size of the sterilizing-grade filters may be the same or tighter than the primary filter (1). Other regulatory bodies (e.g., FDA, EMA and SFDA) have also issued their own guidelines for sterile filtration. According to FDA's aseptic processing guidelines published in 2004, it is recommended that redundant filtration should be considered in many cases where liquid is sterilized by filtration (2). EMA's 2008 GMP guidelines state that because of potential risks of sterilization by filtration, a second filtration step as close to the filling point as possible is advisable (3).

Designing a redundant filtration system that meets regulations and recommendations is challenging. For stainless steel systems, EMA recommends that integrity testing should be performed on sterile filters before use. To do this, filters must be fully wetted without breaching the sterility on the downstream side of the assembly. Many conventional stainless steel facilities employ a "catch can" with a sterile vent filter to collect the initial flush liquid from the wetting step. Prior to use, additional time is required to sterilize, maintain and store the catch can. In addition, use of a catch can constrains the total flush volume that can be used if the filters need to be rewetted (e.g., in a repeated filter integrity test).

Disposable or single-use redundant filtration (SURF) assemblies offer a flexible solution for this relatively complex operation (4). These assemblies can be presterilized by the supplier using gamma irradiation and there is no need for cleaning after use because assemblies are self-contained and entirely disposable.

PROPOSED SINGLE-USE PROCESS SOLUTION: DESIGN CONSIDERATIONS

Many biopharmaceutical companies already use variations of SURF assemblies for final and bulk fill operations. However, preparation and utilization sequences may differ across processes and geographies because of differing national guidelines.

This study reviewed different redundant filtration assembly designs and operating sequences, and proposes a new SURF assembly that has greater operational robustness and minimizes the risk of product contamination. Below are the major design considerations for the assembly (see Figure 1):

A barrier filter (0.2 μm, EMD Millipore) was included in the design as a combined liquid and gas outlet. The barrier filter contains both hydrophilic and hydrophobic sterilizing-grade PVDF membrane, which can exhaust both air and water from the assembly. As a result, it can be used as the initial filter flush outlet and as a sterile air outlet during integrity testing and the filter drying step. Such a filter further solves the problem of flush volume constraints imposed by the catch bag/tank size. The assembly can be wetted and tested for integrity multiple times without breaching the sterile envelope.

Catch bags were attached to the vents of the liquid filters to collect liquid during venting.

Gamma stable vent filters were attached to the bags to enable passage of air during venting.

A hydrophobic PVDF filter was added on the air inlet line to ensure sterility of the air coming into the assembly for integrity testing.

Single-use sterile connectors were used at the assembly's inlet and outlet to assure sterile connections during operation.

The assembly was used in the vertical orientation to achieve better draining after wetting and during product recovery after filtration.

The catch bag on the first liquid filter is primarily in place to avoid the liquid spill that can occur during venting for water flush and product filtration. With some minor modifications, the catch bags on both the first and second liquid filters can also be used for in-process sampling. The catch bag on first liquid filter and the separate air inlet line (with an air filter near the feed inlet) are additional features that are incorporated to ensure cleanliness and ease of operation.

Figure 1

Pre-use, post-sterilization integrity testing of a redundant filtration setup can be challenging. With either stainless steel or a singleuse assembly, it is critical to maintain setup sterility during every step. The efficiency of the filter wetting step is also important to avoid false negative integrity test results. For highvalue products, the drying step after integrity testing is crucial to minimize product dilution. Figure 1 outlines the utilization sequence for SURF assembly before use. Along with the points mentioned above, operator convenience and regulatory compliance were also considered.

Figure 2

A flushing test was conducted to record the reduction of total organic carbon (TOC) and conductivity with flush volume. The filters and assembly were flushed with deionized (DI) water at a flow rate of 250 mL/min for a total of 20 L. The assembly effluent was sampled at 1 L intervals and tested for conductivity and TOC. Analytical results for flush filtrate samples are summarized in Figure 2. At the end of 20 L reverse osmosis (RO)/DI water flush, TOC and conductivity were 0.231 ppm and1.1 μS/cm, respectively.